Abstract C046: Polymorphonuclear myeloid derived suppressor cells die by ferroptosis in the tumor microenvironment

Abstract Myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME) function as an immunosuppressive shield that protects the tumor from the host’s immune system and considered a barrier to effective immunotherapy. Here, we focused on polymorphonuclear (PMN)-MDSCs, the most prevalent MDSCs in the TME, to identify mechanisms regulating their maintenance, turnover, and accumulation. Using four mouse models of cancer including autochthonous pancreatic adenocarcinoma from KPC genetically engineered mice (KrasG12D/p53R172H, PdxCre), we found that PMN-MDSCs spontaneously die by ferroptosis, a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Only PMN-MDSCs within the TME were observed to spontaneously undergo ferroptosis. In mice, ferroptosis-related gene expression in CD11b+L6ClowLy6G+ PMN-MDSC isolated from bone marrow, spleen, and tumor demonstrated tumor-specific ferroptosis across tumor models. In humans, whole transcriptomic analysis of PMN-MDSC sorted from tumors and matched blood of lung cancer patients vs blood of healthy donors revealed up-regulation of genes involved in the regulation of ferroptosis in tumor PMN-MDSC. Ferroptosis gene signatures correlated with the PMN-MDSC signatures in pancreatic cancer patients and was associated with worse overall survival. Thus, ferroptosis is an unappreciated, prominent pathway of cell death of PMN-MDSCs in cancer linked to clinical outcome in patients with pancreatic cancer. Citation Format: Rina Kim, Ayumi Hashimoto, Nune Markosyan, Vladimir A. Tyurin, Yulia Y. Tyurina, Shuyu Fu, Mohit Sehgal, Laura Garcia-Gerique, Gozde Kar, Andrew Kossenkov, Bereket A. Gebregziabher, John W. Tobias, Kristin Hicks, Hui Deng, Laxminarasimha Donthireddy, Andrew Greenberg, Brian Nam, Yulia Nefedova, Valerian E. Kagan, Robert H. Vonderheide, Dmitry Gabrilovich. Polymorphonuclear myeloid derived suppressor cells die by ferroptosis in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C046.